Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance
Stephanie Dillon, … , Derya Unutmaz, Bali Pulendran
Stephanie Dillon, … , Derya Unutmaz, Bali Pulendran
Published April 3, 2006
Citation Information: J Clin Invest. 2006;116(4):916-928. https://doi.org/10.1172/JCI27203.
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Research Article Immunology

Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance

Abstract

Emerging evidence suggests critical roles for APCs in suppressing immune responses. Here, we show that zymosan, a stimulus for TLR2 and dectin-1, regulates cytokine secretion in DCs and macrophages to induce immunological tolerance. First, zymosan induces DCs to secrete abundant IL-10 but little IL-6 and IL-12(p70). Induction of IL-10 is dependent on TLR2- and dectin-1–mediated activation of ERK MAPK via a mechanism independent of the activation protein 1 (AP-1) transcription factor c-Fos. Such DCs stimulate antigen-specific CD4+ T cells poorly due to IL-10 and the lack of IL-6. Second, zymosan induces F4-80+ macrophages in the splenic red pulp to secrete TGF-β. Consistent with these effects on APCs, injection of zymosan plus OVA into mice results in OVA-specific T cells that secrete little or no Th1 or Th2 cytokines, but secrete robust levels of IL-10, and are unresponsive to challenge with OVA plus adjuvant. Finally, coinjection of zymosan with OVA plus LPS suppresses the response to OVA via a mechanism dependent on IL-10, TGF-β, and lack of IL-6. Together, our data demonstrate that zymosan stimulates IL-10+IL-12(p70)–IL-6low regulatory DCs and TGF-β+ macrophages to induce immunological tolerance. These data suggest several targets for pharmacological modulation of immune responses in various clinical settings.

Authors

Stephanie Dillon, Sudhanshu Agrawal, Kaustuv Banerjee, John Letterio, Timothy L. Denning, Kyra Oswald-Richter, Deborah J. Kasprowicz, Kathryn Kellar, Jeff Pare, Thomas van Dyke, Steven Ziegler, Derya Unutmaz, Bali Pulendran

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Figure 10

A model for induction of regulatory DCs, macrophages, and immune tolerance by yeast zymosan.

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A model for induction of regulatory DCs, macrophages, and immune toleran...
Our previous work suggests that Pam-3-cys, which signals DCs through TLR2, induces robust IL-10 and IL-6 but little IL-12(p70) (13, 14). Induction of IL-10 and impaired IL-12(p70) production appear to be critically regulated by ERK activation, which results in the phosphorylation and stabilization of c-Fos, a repressor of IL-12 (13, 14). Such a DC cytokine profile appears to bias toward the Th2 pathway. In the present paper, we demonstrate that zymosan signals to DCs via both TLR2 and dectin-1, inducing the expression of abundant IL-10 but little IL-12(p70) or IL-6. Unlike the case with Pam-3-cys, impairment of IL-12(p70) and induction of c-Fos are not dependent on c-Fos. Induction of IL-10 represses the induction of proinflammatory cytokines, including IL-12, IL-6, and TNF-α. In addition to these effects on DCs, zymosan also induces biologically active TGF-β in macrophages. In this case, the robust induction of IL-10 and TGF-β coupled with impaired induction of IL-6 and IL-12(p70) appears to induce immunological tolerance.